NM_019098.5:c.1208G>A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2
The NM_019098.5(CNGB3):c.1208G>A(p.Arg403Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,558 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_019098.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CNGB3 | ENST00000320005.6 | c.1208G>A | p.Arg403Gln | missense_variant | Exon 11 of 18 | 1 | NM_019098.5 | ENSP00000316605.5 | ||
| CNGB3 | ENST00000681546.1 | n.1028G>A | non_coding_transcript_exon_variant | Exon 6 of 13 | ||||||
| CNGB3 | ENST00000681746.1 | n.1208G>A | non_coding_transcript_exon_variant | Exon 11 of 19 | ENSP00000505959.1 |
Frequencies
GnomAD3 genomes 0.00219 AC: 333AN: 152106Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00458 AC: 1150AN: 251014Hom.: 24 AF XY: 0.00598 AC XY: 812AN XY: 135674
GnomAD4 exome AF: 0.00323 AC: 4711AN: 1460334Hom.: 68 Cov.: 31 AF XY: 0.00410 AC XY: 2981AN XY: 726498
GnomAD4 genome 0.00217 AC: 330AN: 152224Hom.: 5 Cov.: 32 AF XY: 0.00247 AC XY: 184AN XY: 74424
ClinVar
Submissions by phenotype
not provided Benign:4
See Variant Classification Assertion Criteria. -
CNGB3: BS1, BS2 -
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Achromatopsia Pathogenic:2Uncertain:1
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Achromatopsia 3 Pathogenic:1Benign:1
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not specified Uncertain:1Benign:1
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Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251014 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Biallelic mutations in CNBG3 cause autosomal recessive Achromatopsia. However, the c.1208G>A variant has been reported in patients who present with a highly variable range of clinical findings from mild macular dystrophy to severe cone dystrophy with near complete loss of cone function (eg. Michaelides_2004, Lin_2017, Greenberg_2014, Jinda_2021, Burkard_2018, Mayer_2017). One in depth exploration of a large cohort of patients with the variant suggests the variant is a hypomorphic mutation that may cause relatively mild and late-onset or subclinical retinal disease in the homozygous state and may be a cause of digenic triallelic disease due to the correlation of disease severity with CNGB3 and CNGA3 genoytpes (Burkard_2018). Consistent with the clinical findings, a Cngb3-R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3/) mice to obtain triallelic Cnga3+/ Cngb3R403Q/R403Q mutants showed striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice (Burkard_2018). A different functional study found that co-expression of WT CNGA3 and mutant CNGB3/p.R403Q in Xenopus oocytes resulted in formation of heterotetrameric CNG channels with normal surface expression, but increased apparent ligand sensitivity and increased outward rectification, suggesting a gain-of-function mechanism (Bright_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16379026, 30418171, 24504161, 32869108, 28418496, 28795510, 15161866, 37734845). ClinVar contains an entry for this variant (Variation ID: 143154). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Severe early-childhood-onset retinal dystrophy Benign:2
The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and in the heterozygous state in 1 individual with progressive cone dystrophy, segregated with eye disease in 4 relatives from 1 family (PMID: 15161866, 24504161), and has been identified in >2% of South Asian chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg403Gln variant may slightly impact protein function (PMID: 16379026). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive progressive cone dystrophy. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Abnormality of the eye Pathogenic:1
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Retinal dystrophy Uncertain:1
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Retinitis pigmentosa Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at